PROJECTSUMMARY Malignantmelanomaisoneofthemostaggressivetypesofskincancer,causingalarge majorityofskin-cancerrelateddeathsworldwide.Thecombinationofanti-PD-1andanti-CTLA-4 isFDAapprovedformetastaticmelanomaandshowsbetterefficacythananysingleagent alone.Unfortunately,theincidenceofhigh-gradeimmune-relatedadverseevents(irAEs)dueto anti-CTLA-4isapproaching50%.Thereisapressingclinicalneedtodeveloptherapeutic agentsthatmayenhancethetherapeuticeffectofanti-PD1therapywithoutsignificantly increasingtoxicityincancerpatients. CureBiotechisaimedtodevelopanefficacious intratumoralimmunotherapeuticdrugthatcantreatmetastaticmelanomabyitselfandin combinationwithanti-PD1therapy.Resiquimodisatoll-likereceptors(TLR)7and8agonist.It isasecondgenerationimidazoquinolinethatis100timemorepotentthanimiquimod (Aldara). Usinga phaseISBIRgrant,CureBiotechhasdevelopedtwoproprietaryhydrogelbased injectableformulationsforresiquimod.Theformulationsweredesignedtoconfineresiquimod locallyinthetumortodecreasesystemiccytokinereleasesymptoms;?andtobepenetratebetter fibrotictumorstromatoallowastrongerhostimmuneresponse.Ourpreliminarydata demonstratesthatresiquimodtreatmentnotonlyinhibitedmelanomagrowth,butalso suppressedlymphnodemetastasis.Resiquimodincreasesthenumberofintra-tumoralCD45+ leukocytesandenhancestheproliferationandfunctionoftumorantigenrecognizingCD8+ effectorT-cells.Resiquimodshowssynergisticeffectininhibitingmelanomagrowthwhen combinedwithanti-PD1therapy.ThisSBIR phaseIIprojectisaimedto1)studyPD/PKofthe formulatedinjectableresiquimodinmelanomamousemodels;?2)optimize dose/frequency/timingofformulatedresiquimodincombinationwithanti-PD1therapyfor melanoma;?3)performnon-clinicalINDenablingstudiesusingformulatedinjectableresiquimod. ThedeliverablesproposedinthisSBIRgrantrepresentthejumpingstonetowards(i) submissionofFDAINDapplicationofaninjectableresiquimodformulationand(ii)attracting privateequityfundingtosupportPhaseIclinicaltrialofinjectableresiquimodinpatientswith metastaticmelanoma.CureBiotechhasthebusinessdevelopmentexpertise,properintellectual propertyandscientificandpersonnelcapabilitytoachievetheseaimsquicklyandmeticulously. ResultsfromthisproposalwilllayasolidfoundationforFDAINDsubmissionthatwillultimately bringanovelandeffectivetherapytocliniciansandpatientsintheirfightagainstmelanoma.